Increasing evidence is emerging that women are more susceptible to lung cancer than men, suggesting a role for estrogen in the development of the disease. Estrogens are known to act as tumor promoters, through a receptor-mediated mechanism in reproductive organs. These are some reports of estrogen receptor expression in lung tumors, and it is possible that the lung is an estrogen-responsive organ. Recent findings that early menopause is associated with a reduced lung cancer risk and that use of estrogen replacement therapy results in an increased incidence of lung cancer supports this speculation. Additional support for this hypothesis comes from our recent studies, which identified much higher expression of both estrogen receptor5 (ER) alpha, and in some cases ERbeta, in non- small cell lung tumor cells that in normal bronchial epithelial ells or fibroblasts from the lung. Estrogen induced increased cell growth in lung tumor cell lines in vitro and this effect was blocked by the anti-estrogen ICI 182,780. Estrogen also enhanced growth of the lung tumor cell line H23 in immunocompromised mice. Tamoxifen, an inhibitor of estrogen, reduced the in vivo growth of the lung tumor by itself, but enhanced it in the presence of estrogen, suggesting tamoxifen may be a partial agonist in the lung, as it is the uterus and bone. Based on these findings, we hypothesize that estrogen plays a direct role in promoting lung cancer through a receptor mediated mechanism and may be responsible for at least some of the increased risk of women to lung cancer. Estrogenic effects may also help explain the high proportion of women among non- smokers who are diagnosed with lung cancer. PROJECT One of this SPORE application found that expression of the Gastrin-Releasing Peptide Receptor (GRPR) gene was associated with a diagnosis of lung cancer in non-smoking women, and that GRPR expression was enhanced by estrogen in lung cells expressing the ERbeta. This suggests a mechanistic link between estrogen and lung cancer risk. In Project Two of the SPORE, we will examine the role of estrogen in more depth. The Specific Aims are: (1) Determine the frequency and level of expression of the ERalpha and ERbeta in lung tumors and normal lung tissues; (2) examine ability of estrogens to enhance tumor cell proliferation in vitro and in vivo, and ability of anti-estrogens to oppose this effect; (3) determine relative mRNA expression levels of the ERs in biopsies of the human airway of normal and pre-neoplastic histology from current and former smokers; (4) determine effects of estrogen on expression of three genes important in lung cancer proliferation; and (5) examine in on-going clinical trials, and in female subjects from Project one, whether estrogens influence lung cancer risk.